NM_001378454.1:c.6212T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378454.1(ALMS1):c.6212T>C(p.Ile2071Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,212 control chromosomes in the GnomAD database, including 21,161 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2071V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.14 ( 1600 hom., cov: 32)

Exomes 𝑓: 0.16 ( 19561 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.124

Publications

27 publications found

Variant links:

Genes affected

ALMS1 (HGNC:428): (ALMS1 centrosome and basal body associated protein) This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]

ALMS1 Gene-Disease associations (from GenCC):

Alstrom syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Genomics England PanelApp

ALMS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.441972E-4).

BP6

Variant 2-73452739-T-C is Benign according to our data. Variant chr2-73452739-T-C is described in ClinVar as Benign. ClinVar VariationId is 383769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378454.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.6212T>C	p.Ile2071Thr	missense	Exon 8 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.6212T>C	p.Ile2071Thr	missense	Exon 8 of 23	NP_055935.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.6212T>C	p.Ile2071Thr	missense	Exon 8 of 23	ENSP00000482968.1
ALMS1	ENST00000484298.5	TSL:1	c.6086T>C	p.Ile2029Thr	missense	Exon 7 of 22	ENSP00000478155.1
ALMS1	ENST00000423048.5	TSL:1	n.1043T>C		non_coding_transcript_exon	Exon 1 of 9	ENSP00000399833.1

Frequencies

GnomAD3 genomes

AF:

0.138

AC:

20924

AN:

152070

Hom.:

1599

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0811

Gnomad AMI

AF:

0.253

Gnomad AMR

AF:

0.181

Gnomad ASJ

AF:

0.149

Gnomad EAS

AF:

0.00404

Gnomad SAS

AF:

0.129

Gnomad FIN

AF:

0.132

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.171

Gnomad OTH

AF:

0.156

GnomAD2 exomes

AF:

0.145

AC:

35804

AN:

246918

AF XY:

0.147

show subpopulations

Gnomad AFR exome

AF:

0.0795

Gnomad AMR exome

AF:

0.177

Gnomad ASJ exome

AF:

0.142

Gnomad EAS exome

AF:

0.00413

Gnomad FIN exome

AF:

0.131

Gnomad NFE exome

AF:

0.170

Gnomad OTH exome

AF:

0.147

GnomAD4 exome

AF:

0.161

AC:

234698

AN:

1461024

Hom.:

19561

Cov.:

AF XY:

0.161

AC XY:

117148

AN XY:

726836

show subpopulations

African (AFR)

AF:

0.0794

AC:

2659

AN:

33474

American (AMR)

AF:

0.181

AC:

8070

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.143

AC:

3743

AN:

26130

East Asian (EAS)

AF:

0.00403

AC:

160

AN:

39674

South Asian (SAS)

AF:

0.151

AC:

13013

AN:

86246

European-Finnish (FIN)

AF:

0.131

AC:

6941

AN:

52858

Middle Eastern (MID)

AF:

0.188

AC:

1087

AN:

5768

European-Non Finnish (NFE)

AF:

0.171

AC:

190025

AN:

1111790

Other (OTH)

AF:

0.149

AC:

9000

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

12093

24186

36278

48371

60464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6592

13184

19776

26368

32960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.138

AC:

20938

AN:

152188

Hom.:

1600

Cov.:

AF XY:

0.135

AC XY:

10074

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0810

AC:

3366

AN:

41538

American (AMR)

AF:

0.182

AC:

2773

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.149

AC:

517

AN:

3472

East Asian (EAS)

AF:

0.00405

AC:

AN:

5188

South Asian (SAS)

AF:

0.130

AC:

626

AN:

4814

European-Finnish (FIN)

AF:

0.132

AC:

1395

AN:

10604

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.171

AC:

11639

AN:

67984

Other (OTH)

AF:

0.154

AC:

326

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

924

1847

2771

3694

4618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

220

440

660

880

1100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.155

Hom.:

4517

Bravo

AF:

0.140

TwinsUK

AF:

0.164

AC:

609

ALSPAC

AF:

0.168

AC:

649

ESP6500AA

AF:

0.0804

AC:

292

ESP6500EA

AF:

0.167

AC:

1356

ExAC

AF:

0.142

AC:

17109

Asia WGS

AF:

0.0630

AC:

219

AN:

3478

EpiCase

AF:

0.174

EpiControl

AF:

0.177

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Alstrom syndrome (3)

Cardiovascular phenotype (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

1.4

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.023

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.53

MetaRNN

Benign

0.00094

MetaSVM

Benign

-1.0

PhyloP100

-0.12

PrimateAI

Benign

0.40

Sift4G

Benign

1.0

Vest4

0.048

ClinPred

0.0012

GERP RS

-5.1

PromoterAI

-0.012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.032

gMVP

0.018

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over